Substituted amino-phenyl-arsonic acid



Patented Dec. 27, 1932 UNITED STATES PATENT. OFFICE rnrrz MIETZSCH AND HEINRICH KLOS, OF ELBERFELD, GER-MANY, ASSIGNOBS TO WINTEROP CHEMICAL COMPANY, INC., OF NEXV YORK, N. Y., A. CORPORATION OF NEW YORK SUBSTITUTED AltIINO-PHENYL-ARSONIC ACID No Drawing. Application The present invention relates to new sub-- stituted 4z-aminophenyl-arsonic acid compounds.

The 4- (o-aminoor alkylaminoalkylamino) -phenyl-arsonic acids of the formula:

wherein R means H or alkyl and alk means an alkylene group, being obtainable by causing an aminoalkylor alkylaminoalkyl-halide to react on arsanilic acid (see British Patent No. 326,789) are therapeutically valuable products.

In accordance with the present inventlon by acylating the 4- w-amino-alkylamino)- phenyl-arsonic acids or the substitution products thereof there are obtained new compounds of the probable general formula:

wherein Ac stands for a substituted or unsubstituted acyl group, for example, f-ormyl, acetyl, propionyl, isobutyryl, valeryl, benzoyl, aminoacetyl, aminobenzoyl and the like, alk stands for an aliphatic normal or branched alkylene or hydroxy alkylene group, for example, methylene, ethylene, propylene, hydroxy propylene, isobutylene and the like, R means H, OH or halogen, R means H or an alkali or alkaline earth metal. These new compounds possess a less basic character and less solubility than the parent compounds and are distinguished by their stronger action against blood parasites, by a good resorption when taken per 0s and by their intoxicity.

The new process consists in boiling an organic acid of the stated kind with the 4- ((1)- amino alkyl-amino) -phenyl-arsonic acid or a substitution product thereof or in reacting upon the 4- (o-amino alkylamino) -phenyl-arsonic acids or the substitution products thereof with an anhydride or a halide of the organic acids above stated in the customary manner. The new products are preferably salts in the usual manner, if necessary, after filed January 21, 1930, Seria1 No. 422,484, and in Germany January 29, 1929.

adding the requisite amount of a caustic alkali lye, for example, by evaporating the reaction mixture to dryness, dissolving the residue in alcohol and pouring the solution obtained into a suitable organic precipitant, such as ether or acetone. Sometimes, however, the acids themselves separate already during the acylating process.

The new acylated 4-(w-aminoalkyl-amino)-phenyl-arsonic acids and their alkali or alkaline earth metal salts are white or pale colored substances. The acids are soluble in mineral acids forming the corresponding salts with the mineral acids; they are, furthermore, soluble in alkali lyes forming the corresponding alkali metal salts; they are insoluble in acetone and ether and diluted acetic acid and sparingly soluble in water, alkyl and methyl alcohol. The alkali metal salts dissolve in water and alcohols, they are insoluble in acetone and ether and can be precipitated by the latter from their alcoholic solutions.

The invention is illustrated by the following examples without being restricted thereto E mamplel .26 grams of i-aminoethylamino-phenyl-arsonic acid of the probable formula:

obtainable by reacting upon arsanilic acid with w-bromoethyl-phthalimide and sa onifying the intermediate product obtaine are dissolved in 100 cc. of normal caustic soda lye and 150 cc. of water. The solution is heated to about 90 C. and at once mixed with 20 grams of acetic acid anhydride as soon as boiling of the mixture takes place. After removing the excess of acetic acid anhydride the solution is evaporated in vacuo to dryness. The sodium salt of the 4-o-acetylamino-ethylamino)-phenyl-arsonic acid of the probable formula:

is obtained by taking upthe residue in absolute alcohol, filtering the solution and by adding ether to it. It is soluble in water,

methyl and ethyl alcohol, insoluble in acetone and ether, so that it can be precipitated also by acetone from its alcoholic solution. By the addition of hydrochloric or acetic acid to its aqueous solution no precipitate is obtained.v

Example 2.In accordance with the process described in Example 1 from l-(waminopropylamino) -phenyl-arsonic acid the sodium salt'of the 4:-(w-acetylaminopropylamino)-phenylarsonic acid of the probable formula:

is obtained, displaying the same properties as the sodium salt of the corresponding ethyl compound.

Example 3.When replacing the 4-(waminoethylamino)-phenyl-arsonic acid in the process described in Example 1 by the 4l-(waminoethylamino) 2 chloro phenylarsonic acid, the sodium salt of the l-(macetylamino-ethylamino)-2-chloro phenyl arsonic acid of the probable formula:

mc-oo-nreemwmamQ-momm is obtained displaying properties similar to those of the sodium salt of Example 1.

Example {trhen replacing the 4:(maminoethylamino) -phenylarsonic acid in the process described in Example 1 by the l-(waminoethylamino) -52 hydroxy-phenyl-arsonic acid the sodium salt of the 4-(o-acetylaminoethylamino)-Q-hydroxy-phenyl-arsonic acid of the probable formula:

is obtained, displaying properties similar to those of the sodium salt of Example 1.

E trample 5-5.6 grams of l-(o-aminoethylamino)-phenyl-arsonic acid are dissolved in 21.5 cc. of normal caustic soda lye and 60 cc. of water and mixed drop by drop with 4.5 cc. of benzoyl chloride at a temperature of about 50 to 60 C. The benzoylated product formed precipitates on further heating and can be sucked off after cooling. It is dried in vacuo and extracted with ether for removing benzoic acid and three times with 15% acetic acid for removing the unchanged starting material. The residue obtained is the pure 4- (w-benzoylaminoethylamino)-phenyl-arsonic acid of the probable formula:

being easily soluble in diluted caustic alkali and soda lye 1n contradistmction to the starting material and likewise easily soluble in diluted hydrochloride acid, but insoluble in 15% acetic acid wherein the starting material dissolves. It scarcely precipitates from its diluted hydrochloric acid solution by sodium acetate as does the starting material. Furthermore the benzoylated acid is sparingly soluble in water, methyl and ethyl alcoh l, insoluble in acetone and ether.

E wample 6.13 grams of 4- (wanninoethyl amino)-phenyl-arsonic acid are dissolved in 50 cc. or normal caustic soda lye and mixed with 9.5 grams of 3-nitrobenzoyl-chloride at a temperature of about 60 to C. The solution is heated in a boiling water bath until the acylated product has separated. After cooling it is sucked off, dried and extracted with ether and 10% acetic acid. Then the product obtained is dissolved in the calculated amount of normal caustic soda lye and; reduced by heating with iron borings and some diluted acetic acid. Then the solution is sucked off from the iron. sludge and evaporated in vacuo to dryness. The 4c-(w-3- aminobenzoyl-aminoethylamino) -pheny1-ar sonic acid remains in the form of its sodium salt of the probable formula:

as a pale grey powder, being easily soluble in mineral acids.

Example 7.130 grams of aminoaceticacid-chloridehydrochloride are added to a solution of 260 grams of l-(w-aminoethylamino)-phenyl-arsonic acid in 1000 cc. of normal caustic soda lye. The mixture is heated for about 2 to 3 hours in a boiling water bath. After adding 200 cc. of 10% normal caustic soda lye the mixture is evaporated at a low temperature in vacuo. From the residue the sodium chloride formed is separatedby dissolving in absolute alcohol. By precipitating the filtered solution with ether, the sodium salt of the t-(w-aminoa-cetylaminoethylamino) -phenyl-arsonic acid of the probable formula:

is obtained, being a white hygroscopic powder.

E wample 8.-125 grams of valeryl chloride are added to a solution of 260 grams of 1- (o-aminoethylamino) -phenyl-arsonic acid in 1000 cc. of normal caustic soda lye. The mixture is heated to about 60 to 70 C. for about 2 hours. After cooling and adding 100 cc. of 10% normal caustic soda lye the solution is evaporated to dryness in vacuo at a temperature as low as possible. The residue is taken up in absolute alcohol and filtered off from the insoluble sodium chloride. From the solution obtained the sodium salt and of the 4-(w-valerylaminoethylamino)-phenyl-arsonic acid of the probable formula:

and ethyl alcohol and insoluble in acetone and ether.

is precipitated by ether. It is a white hygroscopic powder.

In a similar way, by applying the chlorides of the higher aliphatic carboxylic acids, for example, decyl-aoid chloride, stearic acid chloride and the like, the corresponding acylated 4- (w-aminoalkylarnino) -ars'onic acids are obtainable.

e claim:

1. The compounds of the probable general formula:

wherein Ac stands for an aliphatic acyl group, alk stands for an alkylene radical which may be substituted by a hydroxy group, R stands for hydrogen, halogen or the hydroXy group and R stands for hydrogen, alkali metal or alkaline earth metal, these new compounds being whitish powders of weakly basic character, soluble in alcohol and water and in soluble in acetone and ether.

3. The compounds of the probable general formula:

HaO-CO-NH-alk-NHQ-AsOaHR:

wherein alk stands for an alkylene radical which may be substituted by a hydroxy group, R stands for hydrogen, halogen or the hydroxy group and R stands for hydrogen, alkali metal or alkaline earth metal, these new compounds being whitish powders of weakly basic character, soluble in alcohol and water insoluble in acetone and ether.

4. The compound of the probable formula:

said compound being soluble in water, methyl 5. The compound of the probable formula:

11 0-0O-NH-CH -OHz-OHg-NHOASO HNa said compound being soluble in water, methyl and ethyl alcohol and insoluble in acetone and ether. V

6. The compounds of the probable general formula:

Ac-NH-alk-NHQAsOaHR:

where Ac stands for an aromatic acyl group, alk stands for an alkylene radical which may be substituted by a hydroxy group, R stands for hydrogen, halogen or the hydroXy group and R stands for hydrogen, alkali metal or alkaline earth metal, these new compounds being whitish powders of weakly basic character, soluble in alcohol and water and insoluble in acetone and ether.

7 The compounds of the probable general formula:

wherein alk stands for an alkylene radical which may be substituted by a hydroxy group, R stands for hydrogen, halogen or the hydroXy group and R stands for hydrogen, alkali metal or alkaline earth metal, these new compounds being whitish powders of weakly basic character, soluble in alcohol and water and insoluble in acetone and ether.

8. The compound of the probable formula:

said compound being easily soluble in diluted caustic alkali, soda lye or hydrochloric acid, but insoluble in acetic acid of 15% strength.

In testimony whereof, we afiix our signatures.

FRITZ MIETzsoH. HEINRICH KLos. 

